P530: CPX-351 INDUCTION IS ABLE TO INDUCE MRD NEGATIVE CR IN A SIGNIFICATIVE PROPORTION OF VERY HIGH RISK AML PATIENTS, REGARDLESS OF MUTATIONAL BURDEN, ALLOWING FOR BRIDGING TO TRANSPLANTATION
Authors: Carola Riva, Maria Chies, Paola Minetto, Chiara Vernarecci, Elena Maio, Beatrice Ferro, Giada Zecchetti, Maurizio Miglino, Elisabetta Tedone, Nicoletta Colombo, Enrico Carminati, Clara Nurra, Francesco Puglisi, Antonia Cagnetta, Michele Cea, Roberto Massimo Lemoli, Fabio Guolo
Journal: HemaSphere (2023)

Background: Minimal residual disease (MRD) assessment in Acute Myeloid Leukemia patients (AML) undergoing intensive induction therapy has a high prognostic value in the prediction of relapse and survival. MRD clearance in AML is influenced by different factors. Recent studies following the seminal study by Papaemmanuil et al showed that mutations in TP53, SF3B1, ASXL1, and RUNX1 or high mutational burden in critical genes predicts low rates of MRD negative remission and shorter survival. Those adverse risk mutation are particularly frequent in AML arising from a previous myelodisplastic syndrome (s-AML) or secondary to chemotherapy (t-AML). As Clinical trials evaluating the prognostic relevance of MRD in the context of different molecular subsets mainly involve younger patients affected by de novo AML and receiving conventional 3 + 7 induction, the impact of newer induction approaches is not clear, especially in the setting of s-AML or t-AML. CPX-351 was recently approved for the treatment of s-AML and t-AML. However, only a limited amount of data is available so far on the kinetics and the prognostic value of MRD in elderly s- AML and t-AML patients receiving CPX-351 induction. Aims: The aim of this study was to assess the prognostic impact of mutational burden at diagnosis on MRD clearance and prognosis in a cohort of elderly s-AML or t-AML patients receiving CPX-351 induction chemotherapy. Methods: 61 elderly (>60 year, median age 68, range 60-77) s-AML or t-AML patients treated in our Center with CPX-351 were included. Next generation sequencing (NGS) was performed using the Myeloid Solution panel by SOPHiA Genetics, encompassing 34 critical genes mutations. Sample have been processed on a Illumina MiSeq platform and the analysis performed with SOPHiA DDM® Software. MRD was analysed in all patients achieving complete remission (CR) with multicolour flow-cytometry (MFC), with a threshold of 0.1%. Results: ELN 2022 risk score was high, intermediate and low risk in 31, 27 and 3 patients, respectively. Median mutational burden in NGS analysis was 4 (range 2-8). Most frequent mutations were: RUNX1 (40%), ASXL1 (35%), IDH1 (20%), IDH 2 (15%), TP53 (30%), DNMT3A (12%), TET2 (9%). Three patients died before disease re-assessment, mainly due to infections. After first induction cycle, 50 patients (81%) achieved CR, with a MFC MRD negative in 25/50 responding patients (50%). Both CR rate and MRD negativity probability were not affected by ELN risk group, TP53, RUNX1 or ASXL1 mutations, mutational burden or other analysed variables. CR rate after cycle 2 was 52/61 (85%), with MFC MRD negative in 30 (58%). After a median follow up of 34 months (CI 95%; 21.7 -46.3 months), median OS was 17 months (CI 95% 13-21), whereas 2 year OS was 25%. Multivariate OS analysis revealed that a negative MFC MRD was the strongest independent predictor of longer survival (p<0.05). Notably, OS was not affected by mutational burden (28.1% and 27.3% for patients with less or more than 4 mutations, respectively, p=n.s, Fig.1). In landmark analysis, patients achieving CR and proceeding to allogeneic stem cell transplantation consolidation (HSCT) within 3 months from CR (N=12) had a significantly better outcome if compared to CR patients who did not receive HSCT or proceeded to transplant later (2-year OS: 83.5% and 32.4, respectively, p<0.03). Summary/Conclusion: MRD assessment at TP1 has a strong prognostic value also in the context of elderly s-AML and t-AML patients. CPX-351 resulted in high CR rate with deep MRD responses, regardless of mutational burden, allowing an high number of elderly AML patients to proceed to HSCT. Figure 1: OS according to mutational burdenKeywords: AML, Minimal residual disease (MRD), Therapy-related AML, Molecular markers